Progressive pulmonary disease is the cause of death in over 90% of cystic fibrosis (CF) patients (Koch C. et al., “Pathogenesis of cystic fibrosis,” Lancet 341(8852):1065-9 (1993); Konstan M. W. et al., “Infection and inflammation of the lung in cystic fibrosis,” Davis P B, ed., Lung Biology in Health and Disease, Vol. 64. New York, N.Y.: Dekker: 219-76 (1993)). Pseudomonas aeruginosa is the most significant pathogen in CF lung disease. Over 80% of CF patients eventually become colonized with P. aeruginosa (Fitzsimmons S. C., “The changing epidemiology of cystic fibrosis,” J Pediatr 122(1):1-9 (1993)). The standard therapy for P. aeruginosa endobronchial infections is 14 to 21 days of parenteral antipseudomonal antibiotics, typically including an aminoglycoside. However, parenteral aminoglycosides, as highly polar agents, penetrate poorly into the endobronchial space. To obtain adequate drug concentrations at the site of infection with parenteral administration, serum levels approaching those associated with nephro-, vestibulo-, and oto-toxicity are required (“American Academy of Otolaryngology. Guide for the evaluation of hearing handicap,” JAMA 241(19):2055-9 (1979); Brummett R. E., “Drug-induced ototoxicity,” Drugs 19:412-28 (1980)).
Aerosolized administration of aminoglycosides offers an attractive alternative, delivering high concentrations of antibiotic directly to the site of infection in the endobronchial space while minimizing systemic bioavailability (Touw D. J. et al., “Inhalation of antibiotics in cystic fibrosis,” Eur Respir J 8:1594-604 (1995); Rosenfeld M. et al., “Aerosolized antibiotics for bacterial lower airway infections: principles, efficacy, and pitfalls,” Clinical Pulmonary Medicine 4(2): 101-12 (1997)).
Tobramycin is commonly prescribed for the treatment of serious P. aeruginosa infections. It is an aminoglycoside antibiotic produced by the actinomycete, Streptomyces tenebrarius. Low concentrations of tobramycin (<4 μg/mL) are effective in inhibiting the growth of many Gram-negative bacteria and under certain conditions may be bactericidal (Neu, H. C., “Tobramycin: an overview,” J Infect Dis 134, Suppl: S3-19 (1976)). Tobramycin is poorly absorbed across mucosal surfaces, conventionally necessitating parenteral administration. Tobramycin activity is inhibited by purulent sputum: high concentrations of divalent cations, acidic conditions, increased ionic strength and macromolecules that bind the drug all inhibit tobramycin in this environment. It is estimated that 5 to 10 times higher concentrations of tobramycin are required in the sputum to overcome these inhibitory effects (Levy J. et al., “Bioactivity of gentamicin in purulent sputum from patients with cystic fibrosis or bronchiectasis: comparison with activity in serum,” J Infect Dis 148(6):1069-76 (1983)).
Delivery of the poorly absorbed antibiotic tobramycin to the airway by the aerosol route of cystic fibrosis (CF) patients has been documented using the aerosol route. Much of this work has been done toward treatment of chronic lung infections with P. aeruginosa in cystic fibrosis (CF) patients. A multicenter, double blind, placebo-controlled, crossover trial of 600 mg tid of aerosolized tobramycin for endobronchial infections due to P. aeruginosa in 71 CF patients demonstrated a significant reduction in sputum density of this pathogen as well as improved spirometry in the treatment group. Emergence of P. aeruginosa strains highly resistant to tobramycin (defined as MIC≧128 μg/mL) was comparable in the placebo and treatment groups. The presence in the sputum of Gram-negative organisms other than P. aeruginosa intrinsically resistant to tobramycin occurred with equal frequency during administration of tobramycin or placebo (Ramsey B. et al., “Response to Letter to the Editor: Aerosolized tobramycin in patients with cystic fibrosis,” N Engl J Med 329:1660 (1993)).
Although this regimen was found to be both safe and efficacious, it is costly and inconvenient. A survey of the MICs for P. aeruginosa isolates from initial sputum cultures for patients at the Children's Hospital CF Center, Seattle, Wash., in 1993 found that 90% of isolates had MICs≦16 μg/mL and 98% of all isolates had MICs≦128 μg/mL. This survey suggested that achieving a sputum tobramycin concentration of 128 μg/mL should treat the endobronchial infection in CF patients (Levy J. et al., “Bioactivity of gentamicin in purulent sputum from patients with cystic fibrosis or bronchiectasis: comparison with activity in serum,” J Infect Dis 148(6):1069-76 (1983)).
A randomized, crossover study compared the ability of several nebulizers to deliver tobramycin by measuring peak sputum tobramycin concentrations in samples collected ten minutes after completion of the aerosol dose. This study administered TOBI® tobramycin solution for inhalation, PathoGenesis Corporation, Seattle, Wash. (now Chiron Corporation, Emeryville, Calif.), containing 60 mg/mL tobramycin in 5 mL one quarter (¼) normal saline, using the Pari® LC jet nebulizer, Pari Respiratory Equipment, Inc., Richmond, Va. This delivery system was shown to deliver a mean peak sputum tobramycin concentration of 678.8 μg/g (s.d. 661.0 μg/g), and a median peak sputum concentration of 433.0 μg/g. Only 13% of patients had sputum levels ≦128 μg/g; 87% of patients achieved sputum levels of ≧128 μg/g (Eisenberg, J. et al., “A Comparison of Peak Sputum Tobramycin Concentration in Patients With Cystic Fibrosis Using Jet and Ultrasonic Nebulizer Systems. Aerosolized Tobramycin Study Group,” Chest 111(4):955-962 (1997)). Recently, the Pari® LC jet nebulizer has been modified with the addition of one-way flow valves, and renamed the Pari® LC PLUS. The one-way valves in the Pari® LC PLUS have been described as permitting the delivery of more drug than the Pari® LC jet nebulizer, while decreasing the potential for accidental spillage and allowing for the use of an expiratory filter. Experience has shown that mean peak sputum tobramycin concentrations achieved using the Pari LC PLUS jet nebulizer are significantly higher than those using the Pari® LC jet nebulizer as described in Eisenberg et al. (1997), supra.
Two placebo-controlled, multicenter, randomized, double blind clinical trials of intermittent administration of inhaled tobramycin in cystic fibrosis patients with P. aeruginosa infection were reported in Ramsey, B. W. et al., “Intermittent Administration of Inhaled Tobramycin in Patients with Cystic Fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group.” N. Engl. J. Med. 340(1):23-30 (1999). In these studies, five hundred twenty subjects were randomized to receive either 300 mg inhaled tobramycin or placebo twice daily for 28 days followed by 28 days off study drug. Subjects continued on treatment or placebo for three “on-off” cycles for a total of 24 weeks. Efficacy variables included sputum P. aeruginosa density. Tobramycin-treated patients had an average 0.8 log10 decrease in P. aeruginosa density from Week 0 to Week 20, compared with a 0.3 log10 increase in placebo-treated patients (P<0.001). Tobramycin-treated patients had an average 1.9 log10 decrease in P. aeruginosa density from Week 0 to Week 4, compared with no change in placebo-treated patients (P<0.001).
A preservative-free, stable, and convenient formulation of tobramycin (TOBI® tobramycin solution for inhalation; 60 mg/mL tobramycin in 5 mL of ¼ normal saline) for administration via jet nebulizer was developed by PathoGenesis Corporation, Seattle, Wash. (now Chiron Corporation, Emeryville, Calif.). The combination of a 5 mL BID TOBI dose (300 mg tobramycin) and the PARI LC PLUS/PulmoAide compressor delivery system was approved under NDA 50-753, December 1997, for the management of P. aeruginosa in CF patients, and remains the industry standard for this purpose. The aerosol administration of a 5 ml dose of a formulation containing 300 mg of tobramycin in quarter normal saline for the suppression of P. aeruginosa in the endobronchial space of a patient is disclosed in U.S. Pat. No. 5,508,269, the disclosure of which is incorporated herein in its entirety by this reference.
Although the current conventional delivery systems have been shown to be clinically efficacious, they typically suffer from relatively low efficiency levels in delivering antibiotic solutions to the endobronchial space of a patient, thereby wasting a substantial portion of the nebulized antibiotic formulations and substantially increasing drug delivery costs. The low efficiency of current conventional delivery systems requires patients to devote relatively long time periods to receive an effective dose of the nebulized antibiotic formulations, which can lead to decreased patient compliance. Accordingly, there is a need for new and improved methods and devices for the delivery of aminoglycoside antibiotic compounds to a patient by inhalation to reduce administration costs, increase patient compliance and enhance overall effectiveness of the inhalation therapy.